Ibuprofen disposition in obese individuals
Eleven obese subjects (weight 114 +/- 11 kg, mean +/- SE) and 11 age-matched subjects with normal body weight (61 +/- 3 kg) were given 600 mg of ibuprofen orally after an overnight fast. Peak ibuprofen concentration was significantly decreased in obese subjects (P less than 0.02), although the time from administration to peak concentration was not different. Ibuprofen volume of distribution was increased in obese subjects, and this increased distribution correlated positively with body weight (r = 0.82; P less than 0.001). Volume of distribution corrected for body weight was decreased in obese subjects, and this decrease correlated negatively with body weight. Ibuprofen clearance was also increased in obese subjects; the increase correlated positively with body weight (r = 0.81; P less than 0.001). Since the independent variables, volume of distribution and clearance, were increased in parallel in the obese subjects, the dependent variable, elimination half-life, was unchanged. Using mean values of distribution calculated from the 2 groups, ibuprofen distribution into body weight in excess of ideal body weight was found to be approximately 0.44 times as extensive as the distribution into ideal body weight. Furthermore, ibuprofen clearance increased in parallel with the volume of distribution and total body weight. Clinically, these data indicate that in obese patients, the ibuprofen dose may be increased without changing the dose interval, in order to achieve necessary plasma concentrations.
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- "Vc; Volume of Central Compartment; # Calculated by GastroPlusͿ 7.0 * Calculated by ADMET Predictor; a Ref (Oliary et al., 1992); b Ref (Perez de la Cruz Moreno et al., 2006); c Ref(Avdeef et al., 1998); d Ref (Domanska et al., 2009); e Ref (Abernethy and Greenblatt, 1985);f Ref (Geisslinger et al., 1995); g Ref (Cordero et al., 1997); h Ref (Beetge et al., 2000); i Ref (Kasim et al., 2004); j Ref (GlaxoSmithKline, 2009); k Ref (Planinsek et al., 2011); l Ref(Loftsson et al., 2008); m Ref (Huang et al., 1986); n Ref (Vertzoni et al., 2010); o Ref (Peeters et al., 2008);p Ref (Mannisto et al., 1982); q Ref (Baxter et al., 1986); r Ref (Keating and Croom, 2007); s Ref (Fei et al., 2013); t Ref (Ige et al., 2013); u Ref (Yun et al., 2006); v Ref (Hooper et al., 1991); w Ref (Prajapati et al., 2012); x Ref (Dressman and Reppas, 2000); "
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ABSTRACT: The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a Sub-classification extension of the original BCS Classification.This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology (). Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro-in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance.
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ABSTRACT: Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.
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ABSTRACT: Drug disposition for many drugs has now been studied in obese individuals and some general conclusions can be drawn. Absorption of drugs evaluated to date is unchanged due to obesity. Apparent volume of distribution is greatly increased for some drugs including most benzodiazepines, thiopentone, phenytoin, verapamil and lignocaine (lidocaine). Modest increases in volume of distribution have been noted for methylxanthines, aminoglycosides, vancomycin, ibuprofen, prednisolone and heparin. Distribution of digoxin, cimetidine and procainamide is unchanged in obesity. The mechanism for the increased distribution of some drugs and unchanged distribution of others in obesity is unclear at present. It may be in part due to the lipophilic character of the drug molecule; however, other complex and as yet poorly understood factors contribute to the variability in drug distribution in obese patients.
Protein binding of drugs bound to albumin is not dramatically changed in obesity. In contrast, some studies report that drugs bound to α1-acid glycoprotein (AAG) may have increased binding that is related to increased serum AAG concentration; however, this is not a consistent finding.
Oxidative drug biotransformation is minimally changed in obesity with the exceptions of ibuprofen and prednisolone, for which clearance increases as a highly correlated function of total bodyweight. Drug conjugation uniformly increases as a function of bodyweight in obesity, with paracetamol (acetaminophen), lorazepam and oxazepam having been studied. Drug acetylation may be unchanged in obesity, with only procainamide evaluated at this time. High clearance drugs, including lignocaine, verapamil and midazolam, have no change in clearance in obese individuals compared to normal bodyweight controls. Renal clearance of drugs is little changed for some drugs evaluated (digoxin, cimetidine), and increased for others (aminoglycosides, unmetabolised procainamide).
Characterisation of appropriate animal models of obesity is underway to clarify the mechanisms for these in vivo pharmacokinetic observations in obese man. Two models, the Zucker obese and the obese cafeteria-fed male Sprague-Dawley rat, have provided preliminary physiological pharmacokinetic data with evaluations of theophylline, phenobarbitone and verapamil. The Zucker genetically obese rat may be somewhat limited as a model due to impairment in renal function and impairment in capacity for regulation of cytochrome P-450 activity in obese animals that differs from heterozygous lean Zucker rats. Limitations of the cafeteria-fed Sprague-Dawley rat model of obesity identified to date are that only male rats will eat to a significant extent of obesity, the alteration in animal diet required to achieve obesity is difficult to properly control in pharmacokinetic studies in which dietary alteration in man and animals is well known to change oxidative drug clearance, and that at least 3 months of feeding the specialised diet are required to achieve bodyweight at least 40% in excess of control animals. With further identification and understanding of the limitations of these models, a mechanistic understanding of pharmacokinetic alterations associated with human obesity may be forthcoming.
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